Oxygen radicals in experimental shock: effects of spin-trapping nitrones in ameliorating shock pathophysiology

Circulatory shock is accepted as a consequence of an acute oxygen radical overgeneration. Spin-trapping nitrones inactivate free radicals by forming relatively stable adducts.

Three spin-trapping nitrones (N-tert-phenyl-butyl-nitrone; alpha-4-pyridyl-oxide-N-tert-butyl-nitrone; 5-5,dimethyl,1,pyrroline-N-oxide) were tested regarding their role in the pathophysiology and evolution of circulatory shock in rats.

Prospective, randomized, controlled trial of spin-trapping nitrones in rats experiencing three different models of circulatory shock.

In the first group, endotoxic, traumatic, and mesenteric artery occlusion shock (all 100% lethal in control experiments) was prevented by the ip administration of N-tert-phenyl-butyl-nitrone (150 mg/kg); alpha-4-pyridyl-oxide-N-tert-butyl-nitrone (100 mg/kg); or 5-5,dimethyl,1,pyrroline-N-oxide (100 mg/kg). However, the evolution of shock was unaffected by the same compounds when all three nitrones had been previously inactivated by exposure to light and air. In the second group, microcirculatory derangements that were provoked by endotoxin and were observed in the mesocecum of rats were completely prevented by pretreatment with either peritoneal administration of each of the three nitrones or by their topical application to the microscopic field. While the rats survived after systemic treatment, those rats receiving topical nitrones died from endotoxic shock. In the third group, cell-membrane stiffness (a sign of peroxidative damage) was measured by spin-probes and electron-spin resonance in mitochondrial and microsomal membranes. Cell membranes obtained from shocked rats were more rigid than those membranes of controls. However, the membranes obtained from rats that were submitted to trauma or endotoxin after pretreatment with N-tert-phenyl-butyl-nitrone had normal stiffness. The fourth group of experiments was carried out to quantify ethane (one of the final products of lipid peroxidation) in the exhaled air of shocked rats. Ethane concentrations increased in direct proportion to the worsening of the condition. Pretreatment of the rats with N-tert-phenyl-butyl-nitrone prevented such an increase.

Since nitrones are effective inactivators of oxygen-radicals, or of their secondary radicals, these data confirm the relationship between oxygen-radicals and experimental shock. The therapeutic use of spin-trapping nitrones should possibly be considered for future use in shock.